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Blood, 15 December 2001, Vol. 98, No. 13, pp. 3685-3692
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Congenital afibrinogenemia: mutations leading to premature
termination codons in fibrinogen A -chain gene are not associated
with the decay of the mutant mRNAs
Rosanna Asselta,
Stefano Duga,
Silvia Spena,
Elena Santagostino,
Flora Peyvandi,
Gavino Piseddu,
Roberto Targhetta,
Massimo Malcovati,
Pier Mannuccio Mannucci, and
Maria Luisa Tenchini
From the Department of Biology and Genetics for Medical
Sciences, University of Milan, Italy; Angelo Bianchi Bonomi Hemophilia
and Thrombosis Center and Fondazione Luigi Villa, Department of
Internal Medicine, University of Milan and IRCCS Maggiore Hospital,
Milan, Italy; Servizio di Coagulazione, Servizio di Prevenzione,
Diagnosi e Terapia delle Malattie Emorragiche e Trombotiche, Azienda
USL n.1, Sassari, Italy; Centro Emofilia e Malattie
Emorragiche, University of Cagliari, Cagliari, Italy.
Congenital afibrinogenemia is a rare coagulation disorder with
autosomal recessive inheritance, characterized by the complete absence
or extremely reduced levels of fibrinogen in patients' plasma and
platelets. Eight afibrinogenemic probands, with very low plasma
levels of immunoreactive fibrinogen were studied. Sequencing of the
fibrinogen gene cluster of each proband disclosed 4 novel point
mutations (1914C>G, 1193G>T, 1215delT, and 3075C>T) and 1 already
reported (3192C>T). All mutations, localized within the first 4 exons
of the A -chain gene, were null mutations predicted to produce
severely truncated A-chains because of the presence of
premature termination codons. Since premature termination codons are frequently known to affect the metabolism of the corresponding messenger RNAs (mRNAs), the degree of stability of each mutant mRNA
was investigated. Cotransfection experiments with plasmids expressing
the wild type and each of the mutant A-chains, followed by RNA
extraction and semiquantitative reverse-transcriptase-polymerase chain
reaction analysis, demonstrated that all the identified null
mutations escaped nonsense-mediated mRNA decay. Moreover, ex vivo
analysis at the protein level demonstrated that the presence of each
mutation was sufficient to abolish fibrinogen secretion.
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